Quinoline derivatives and their use as antagonists of leukotriene d4

ABSTRACT

This invention relates to quinoline derivatives (I), their use in the treatment of hypersensitive ailments and a pharmaceutical composition containing the same. They are especially valuable as lipoxygenase inhibitors and/or leukotriene antagonists, typically antagonists of leukotriene D4, possessing anti-inflammatory and anti-allergic properties. &lt;CHEM&gt;  a is 0-2;  b is 0-1;  c is 0-4;  d is 0-5;  e is 0-4;  f is 0-5;  n is 0-2; R is independently hydrogen, alkyl, hydroxy, alkoxy, carboxy, carbalkoxy, halo, nitro, haloalkyl, cyano or acyl; R min  is independently hydrogen, alkyl, hydroxy, alkoxy, halo or haloalkyl;  R1 is independently hydrogen, alkyl or aralkyl;  R2 is -(CH2)x - X, where x is 0-3; X is hydrogen, alkyl, alkenyl, cycloalkyl, aryl aralkyl, hydroxy, alkoxy, aralkoxy, amino, mono-and di-alkylamino, aralkylamino, acylamino, carbamyl, carboxy, carbalkoxy, tetrazolyl, or acylsulfonamido; vicinal R2 groups together may be (CH2)y - where y is 1-4, thus forming a 3-6 membered ring; geminal R1 and R2 groups may together form a spiro substituent, -(CH2)z -, where z is 2 to 5; geminal R1 or R1 and R2 groups may together form an alkylidenyl substituent, =CHR1;   Z is -COOR1, CN, - @NHSO2R3, -@N(R1)2, -OR1, tetrazolyl or substituted tetrazolyl where the substituent may be alkyl, carboxyalkyl or carbalkoxyalkyl; and R3 is hydrogen, alkyl, haloalkyl, phenyl or benzyl; or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of application Ser. No. 07/116,420, filedNov. 3, 1987, now U.S. Pat. No. 4,920,132.

FIELD OF INVENTION

This invention relates to quinolinyl phenyl compounds and their use asvaluable pharmaceutical agents, particularly as lipoxygenase inhibitorsand/or leukotriene antagonists possessing anti-inflammatory andanti-allergic properties.

SUMMARY OF THE INVENTION

This invention relates to the compounds described by the general FormulaI and to therapeutic compositions comprising as active ingredient acompound of Formula I: ##STR1## where: A is O or S;

B is O, S, SO, SO₂ NR₁, ##STR2## D is O, S, NR₁, ##STR3## or a chemicalbond; E is a chemical bond or ##STR4## a is 0-2; b is 0-1;

c is 0-4;

d is 0-5;

e is 0-4;

f is 0-5;

n is 0-2;

R is independently hydrogen, alkyl, hydroxy, alkoxy, carboxy,carbalkoxy, halo, nitro, haloalkyl, cyano or acyl;

R' is independently hydrogen, alkyl, hydroxy, alkoxy, halo or haloalkyl;

R₁ is independently hydrogen, alkyl or aralkyl;

R₂ is --(CH₂)_(x) --X, where x is 0-3;

X is hydrogen, alkyl, alkenyl, cycloalkyl, aryl aralkyl, hydroxy,alkoxy, aralkoxy, amino, mono-and di-alkylamino, aralkylamino,acylamino, carbamyl, carboxy, carbalkoxy, tetrazolyl, oracylsulfonamido;

vicinal R₂ groups together may be (CH₂)_(y) --where y is 1-4, thusforming a 3-6 membered ring;

geminal R₁ and R₂ groups may together form a spiro substituent,--(CH₂)_(z) --, where z is 2 to 5;

geminal R₁ or R₁ and R₂ groups may together form an alkylidenylsubstituent, ═CHR₁ ;

Z is --COOR₁, CH, ##STR5## --OR₁, tetrazolyl or substituted tetrazolylwhere the substituent may be alkyl, carboxyalkyl or carbalkoxyalkyl;

R₃ is hydrogen, alkyl, haloalkyl, phenyl or benzyl; and pharmaceuticallyacceptable salts thereof.

The compounds of Formula I contain at least three aromatic rings, whichmay be designated as shown in Formula II below, and for which theirsubstitution pattern along the chain with respect to each other is shownalso below. ##STR6##

The substitution pattern of the quinoline ring, that is Ring I, ispreferably at the 2- position for extending the side chain. As this sidechain progresses from the quinoline ring, the two phenyl rings,designated Ring II and Ring III may be substituted along the chain inthe ortho, meta or para positions with respect to each other and Ring IImay also be substituted in the ortho, meta and para positions in respectto the quinoline ring.

The preferred substitution pattern for ring II is meta or para, that is:##STR7##

Ring III may be substituted equally in the ortho, meta or parapositions, that is: ##STR8##

Further preferred compounds of this invention are described by Formula Vbelow: ##STR9##

where c+d=1-3 and R, R₁, R₂, e, f, n, D, E and Z are as described above.

The preferred compounds of Formula V are those where Z is --COOR₁ ;--CN; ##STR10## or tetrazolyl.

In addition, the present invention relates to the method of using thesecompounds as lipoxygenase inhibitors and/or leukotriene antagonistspossessing anti-inflammatory and anti-allergic properties.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Alkyl", either alone or with various substituents defined herein, meansa saturated aliphatic hydrocarbon, either branched or straight chained.A "loweralkyl" is preferred having about 1 to about 6 carbon atoms.Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl,sec-butyl, t-butyl, amyl, hexyl, etc.

"Alkoxy" refers to a loweralkyl-O-group.

"Alkenyl" refers to a hydrocarbon having at least one point ofunsaturation and may be branched or straight chained. Preferred alkenylgroups have six or less carbon atoms and include vinyl, allyl, ethynyl,isopropenyl, etc.

"Aralkyl" means an alkyl group substituted by an aryl radical. Thepreferred aralkyl groups are benzyl or phenethyl.

"Cycloalkyl" means a saturated monocyclic hydrocarbon ring having 3 toabout 6 carbon atoms. Preferred groups include cyclopropyl, cyclohexyl,etc.

"Acyl" means an organic radical derived from an organic acid by removalof its hydroxyl group. Preferred acyl groups are groups derived fromcarboxylic acids. More preferred are the lower alkanoyl or benzoylgroups such as acetyl, propionyl benzoyl, etc.

"Halo" means a halogen. Preferred halogens include, chloride, bromideand fluoride. The preferred haloalkyl group is trifluromethyl.

The compounds of this invention may be prepared in segments as is commonto a long chain molecule. Thus it is convenient to synthesize thesemolecules by employing condensation reactions at the A, B and D cites ofthe molecule. For this reason the present compounds may be prepared byart recognized procedures from known compounds or readily preparableintermediates. Exemplary general procedures are as follows and are shownwhere R, R', R₁ and R₂ are all hydrogen; b, d, and e are 0; a, c, and fare 1; or b, c, e and f are 0 and a and d are 1. B is O, S or NR₁ and Zis --CN, --COOR₁ or tetrazolyl. Thus, in order to prepare the compoundof the below formula ##STR11## the following reactions or combinationsof reactions may be employed: ##STR12## where: R, R', R₁, R₂, a, b, c,d, e, f, n, A, and D are as defined above, B is O or S; E is a chemicalbond; Z is --CN, --COOR₁ or tetrazolyl, and L is a leaving group, suchas halo, tosylate, or mesylate. Where B is O or S, any base normallyemployed to deprotonate an alcohol or thiol may be used, such as sodiumhydride, sodium hydroxide, triethyl amine, sodium bicarbonate ordiisopropyl/ethylamine.

Reaction temperatures are in the range of room temperature to reflux andreaction times vary from 2 to 96 hours. The reaction is usually carriedout in a solvent that will dissolve both reactants and is inert to bothas well. Solvents include, but are not limited to, diethyl ether,tetrahydrofuran, N,N-dimethyl formamide, dimethyl sulfoxide, dioxane andthe like.

In the case where B is SO or SO then treatment of the thio compound withm-chlorobenzoic acid or sodium periodate results in the sulfinylcompound. Preparation of the sulfonyl compound may be accomplished byknown procedures such as dissolving the sulfinyl compound in acetic acidand treating with 30% H₂ O₂.

These compounds where B is ##STR13## may be prepared by the followingreaction sequence; ##STR14##

Condensation of the aldehyde with 1,3-propanedithiol results in thedithiane compound. This may be carried out in chloroform at reducedtemperatures (-20° C.) while bubbling HCl gas into the reaction mixture.The dithiane compound is then treated with N-butyl lithium in nonpolarsolvent at -78° C. and then reacted with the substituted benzylchloride. This results in addition of the Ring III to the molecule. Thedithiane moiety is then treated with a mercuric chloride-mercuric oxidemixture to form the complex which is then split off leaving the desiredcompound.

Those compounds where D and/or E are ##STR15## are prepared by reactingthe appropriate aldehyde or ketone with a substituted Wittig reagent ofthe formula ##STR16## where Z is cyano or carbalkoxy.

The tetrazole may be formed from the nitrile at various stages of thesynthesis by treatment with hydrazoic acid formed in situ from sodiumazide and an acid.

When B is ##STR17## then condensation of the acid halide with theappropriate aniline will give the desired compound as shown below in thefollowing scheme. ##STR18##

The products of this invention may be obtained as racemic mixtures oftheir dextro and levorotatory isomers since at least one asymmetriccarbon atom may be present. When two asymmetric carbon atoms are presentthe product may exist as a mixture of two diastereomers based on syn andanti configurations. These diastereomers may be separated by fractionalcrystallization. Each diastereomer may then be resolved into dextro andlevorotatory optical isomers by conventional methods.

Resolution may best be carried out in the intermediate stage where it isconvenient to combine the racemic compound with an optically activecompound by salt formation, ester formation, or amide formation to formtwo diasteromeric products. If an acid is added to an optically activebase, then two diastereomeric salts are produced which possessesdifferent properties and different solubilities and can be separated byfractional crystallization. When the salts have been completelyseparated by repeated crystallization, the base is split off by acidhydrolysis and the pure d and 1 acids are obtained.

The present compounds form salts with acids when a basic amino functionis present and salts with bases when an acid function, i.e., carboxyl,is present. All such salts are useful in the isolation and/orpurification of the new products. Of particular value are thepharmaceutically acceptable salts with both acids and bases. Suitableacids include, for example, hydrochloric, sulfuric, nitric,benzenesulfonic, toluenesulfonic, acetic, maleic, tartaric and the likewhich are pharamaceutically acceptable. Basic salts for pharmaceuticaluse are the Na, K Ca and Mg salts.

Various substituents on the present new compounds, e.g., as defined inR, R₁ and R₂ can be present in the starting compounds, added to any oneof the intermediates or added after formation of the final products byknown methods of substitution or conversion reactions. If thesubstituents themselves are reactive, then the substituents canthemselves be protected according to the techniques known in the art. Avariety of protecting groups known in the art, may be employed. Examplesof many of these possible groups may be found in "Protective Groups inOrganic Synthesis" by T. W. Green, John Wiley and Sons, 1981. Forexample, nitro groups can be added to the aromatic ring by nitration andthe nitro group converted to other groups, such as amino by reduction,and halo by diazotization of the amino group and replacement of thediazo group. Acyl groups can be substituted onto the aryl groups byFriedel-Crafts acylation. The acyl groups can then be transformed to thecorresponding alkyl groups by various methods, including theWolff-Kishner reduction and Clennenson reduction. Amino groups can bealkylated to form mono and dialkylamino groups; and mercapto and hydroxygroups can be alkylated to form corresponding ethers. Primary alcoholscan be oxidized by oxidizing agents known in the art to form carboxylicacids or aldehydes, and secondary alcohols can be oxidized to formketones. Thus, substitution or alteration reactions can be employed toprovide a variety of substituents throughout the molecule of thestarting material, intermediates, or the final product.

The compounds of the present invention have potent activity asleukotriene antagonists and as such possess therapeutic value in thetreatment of inflammatory conditions and allergic responses such asanaphlaxis and asthma.

Protocol for SRS-A (slow reacting substance of anaphylaxis) Antagonist

Leukotrienes, the products of the 5-lipoxygenase pathway of arachidonicacid metabolism, are potent contractile agents with a variety of smoothmuscle preparations. Thus, it has been hypothesized that theleukotrienes contribute significantly to the pathophysiology of asthma.This protocol describes an in vitro assay used to test compounds whichspecifically antagonize the actions of leukotrienes.

Peripheral strips of guinea pig lungs are prepared and hung in tissuebaths (Metro #ME-5505, 10 ml) according to the published procedure --(Proc. Nat'l. Acad. Sci., U.S.A. Volume 77, pp. 4354-4358, 1980). Thestrips are thoroughly rinsed in Assay Buffer and then connected withsurgical silk thread support rods from the tissue baths. The rods areadjusted in the baths and the strips connected to the pressuretransducers (Grass FT 103 or Gould US-3). The tissue baths are aeratedwith 95% oxygen -- 5% carbon dixoide and maintained at 37° C. The assaybuffer has been made as follows: for each liter of buffer the followingare added to approximately 800 ml of water distilled in glass-6.87 gNaCl, 0.4 g MgSO₄ ·7H₂ O, and 2.0 g D-glucose. Then a solution of 0.368g CaCl₂ ·H₂ O in 100 ml glass-distilled water is slowly added to thebuffer. Sufficient water is added to adjust the volume to 1 liter, andthe solution is aerated with 95% oxygen -- 5% carbon dioxide. Usually 10liters of buffer are used for an experiment with 4 tissues. After thetissues have been repeatedly washed and allowed to equilibrate in thetissue bath, they are challenged with 1 μM histamine. After maximumcontractions have been obtained, the tissues are washed, and allowed torelax back to baseline tension. This histamine challenge procedure isrepeated at least 1 to 2 more times to obtain a repeatable controlresponse. The average response to 1 μM histamine for each tissue is usedto normalize all other challenges.

Responses of each tissue to a predetermined concentration of leukotrieneare then obtained. Usually test compounds are examined initially at 30μM on resting tension of the tissues without any added agonist orantagonist to determine if the compound has any possible intrinsicactivity. The tissues are washed and the test compound is added again.Leukotriene is added after the desired pre-incubation time. Theintrinsic activity of the compounds, and their effect onleukotriene-induced contractions are then recorded.

The results of this test for the compounds of the this inventionindicates that these comopunds are considered to be useful leukotrieneantagonists.

Inhibition of (³ H)-LTD₄ Binding Membranes from Guinea Pig Lung.

A. Preparation of the Crude Receptor Fraction

This procedure was adapted from Mong et al (1984). Male guinea pigs aresacrificed by decapitation and their lungs are quickly removed andplaced in a beaker containing ice-cold homogenization buffer. The lungsare separated from connective tissue, minced with scissors, blotted dryand weighed. The tissue is then homogenized in 40 volumes (w/v) ofhomogenization buffer with a Polytron at a setting of 6 for 30 seconds.The homogenate is centrifuged at 1000×g for 10 minutes (e.g. 3500 RPM,SS-34 Rotor). The supernate is filtered through two layers of cheesecloth and centrifuged at 30,000×g for 30 minutes (e.g. 18,500 RPM SS-34Rotor), after which the resulting pellet is resuspended in 20 volumes ofassay buffer by hand homogenization using a Dounce homogenizer. Thefinal pellet is resuspended in 10 volumes of assay buffer and kept at 4°C. until use.

B. Binding Assay

Each assay tube (16×100 mm) contains the following:

490 μL Assay Buffer

10 μL Test compound or solvent

100 μL ³ H-LTD₄ (ca. 17,500 DMP)

400 μL Protein preparation

Incubations are done at 25° C. for 20 minutes in a shaking water bath.Reactions are started by the addition of the protein preparation. At theend of the incubation time, 4.0 ml of cold wash buffer is added to thetube. After being vortexed, the contents of the tube are immediatelypoured over a Whatman GF/C Filter (25 mm diameter) which is sitting in avacuum manifold (e.g., Millipore Model No. 3025 manifold) to which apartial vacuum is applied. The filters are immediately washed with anadditional 15 ml of cold buffer. The filter are transferred to 7 mlplastic scintillation vials to which 6.0 ml of appropriate scintillationfluid (e.g., Scintiverse) is added. After being allowed to equilibratefor 4-6 hours, the radioactivity is counted with a liquid scintillationcounter appropriately set for tritium.

The required control assay tubes include the following:

(a) Total Binding: No test compound is added; buffer is substituted.

(b) Non-Specific Binding: Non-labeled ligand is added at a concentrationof 1 μM.

(c) Solvent Controls: If test compound is dissolved in a solvent,controls for both Total Binding and Non-Specific Binding containingsolvent but no compounds are required.

The results of this test indicate that the compounds of this inventionexhibit valuable properties which are useful in the treatment ofinflammatory conditions and allergic responses.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepthelially including transdermal, opthalmic, sublingual andbuccal; topically including opthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 6% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 50 and 300 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens apreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountemployed. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablynixed with a surfactant such as hydroxypropyl-cellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exits. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administer-ed to amammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and itwill vary with the form of administration and the particular compoundchosen, and also, it will vary with the particular patient undertreatment. He will generally wish to initiate treatment with smalldosages by small increments until the optimum effect under thecircumstances is reached. The therapeutic dosage will generally be from0.1 to 100 mM/day or from about 0.1 mg to about 50 mg/kg of body weightper day and higher although it may be administered in several differentdosage units. Higher dosages are required for oral administration.

The compounds of the present invention may be prepared by the followingrepresentative examples.

EXAMPLE 1 3-(2-Quinolinylmethyloxy)Benzyl Alcohol

A mixture of 12.8 g (0.06 mol) of 2-quinolinylmethyl chloride HCl, 7.5 g(0.06 mol) of 3-hydroxybenzyl alcohol, and 18 g of potassium carbonatein 50 ml of DMF is heated at 70° C. overnight. The reaction mixture ispoured into water, and the precipitated product is collected, filteredand dried to give 3-(2-quinolinylmethyloxy)benzyl alcohol.

EXAMPLE 2

When 2-quinolinylmethyl chloride of Example 1 above is replaced by thequinoline compounds of Table I below then the corresponding product isobtained.

TABLE I

2-chloromethylquinoline

2-bromomethylquinoline

2-(1-chloroethyl)quinoline

2-(2-chloroethyl)quinoline

2-bromoethylquinoline

3-chloromethylquinoline

4-chloromethylquinoline

2-(β-chloroethyl)quinoline

2-(β-chloropropyl)quinoline

2-(β-chloro-β-phenethyl)quinoline

2-chloromethyl-4-methylquinoline

2-chloromethyl-6-methylquinoline

2-chloromethyl-8-methylquinoline

2-chloromethyl-6-methoxyquinoline

2-chloromethyl-6-nitroquinoline

2-chloromethyl-6,8-dimethylquinoline

EXAMPLE 3

When 3-hydroxybenzyl alcohol of Example 1 above is replaced by thecompounds of Table II below then the corresponding product is obtained.

TABLE II

1,2-benzenediol

1,3-benzenediol

1,4-benzenediol

2-mercaptophenol

3-mercaptophenol

4-mercaptophenol

1,3-dimercaptobenzene

1,4-dimercaptobenzene

3-hydroxybenzyl alcohol

3-hyroxyethylphenol

4-hydroxybenzyl alcohol

4-hydroxyethylphenol

2-methylresorsinol

5-methylresorsinol

5-methoxyresorsinol

5-methyl-1,4-dihydroxybenzene

3-(N-acetylamino)phenol

3-(N-acetylamino)benzyl alcohol

2-hydroxy-α-methylbenzyl alcohol

2-hydroxy-α-ethylbenzyl alcohol

2-hydroxy-α-propylbenzyl alcohol

3-hydroxy-α-methylbenzyl alcohol

3-hydroxy-α-ethylbenzyl alcohol

3-hydroxy-α-propylbenzyl alcohol

4-hydroxy-α-methylbenzyl alcohol

4-hydroxy-α-ethylbenzyl alcohol

4-hydroxy-α-propylbenzyl alcohol

EXAMPLE 4

When the compounds of Table I, Example 2 are reacted with the compoundsof Table II, Example 3 under the conditions of Example 1 thencorresponding products are obtained.

EXAMPLE 5 3-(2-Quinolinylmethyloxy)Benzyl Chloride

To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzylalcohol in 150 ml of CHCl3 is added dropwise 7.5 ml of thionyl chlorideduring 10 min. The reaction mixture is stirred for 4 hours at roomtemperature, and then washed with NaHCO3 solution. The organic solutionis separated, dried, and evaporated to give3-(2-quinolinylmethyloxy)benzyl chloride which is used without furtherpurification in the next step.

EXAMPLE 6

When the compounds prepared by Examples 2-4 are used in place of3-(2-quinolinymethyloxy)benzyl alcohol in Example 5, then thecorresponding chloride is prepared.

EXAMPLE 7 3-[3-(2-Quinolinylmethyloxy)benzyloxy]Benzonitrile

A solution of 0.65 g (5.4 mmol) 3-hydroxybenzoinitirle, 1.5 g (5.3 mmol)of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) ofpotassium carbonate in 15 ml of DMF is heated at 60° C. overnight. Thereaction mixture is poured into water. The precipitated product iscollected on a filter and purified by dry column chromatography to give3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (M.P. 86°-87° C.)

EXAMPLE 8

When 3-hydroxybenzonitrile of Example 7 above is replaced by thecompounds of Table III below then the corresponding product is obtained.cl TABLE III

2-hydroxybenzonitrile

3-hydroxybenzonitrile

4-hydroxybenzonitrile

2-cyanomethylphenol

3-cyanomethylphenol

4-cyanomethylphenol

2-cyanoethylphenol

3-cyanoethylphenol

4-cyanoethylphenol

2-cyanoethylphenol

3-cyanopropylphenol

4-cyanopropylphenol

2-cyanopropylphenol

3-cyanobutylphenol

4-cyanobutylphenol

2-methyl-3-hydroxybenzonitrile

4-methyl-3-hydroxybenzonitrile

5-methyl-3-hydroxybenzonitrile

2-methyl-4-hydroxybenzonitrile

3-methyl-4-hydroxybenzonitrile

5-methyl-4-hydroxybenzonitrile

4-methoxy-3-hydroxybenzonitrile

3-methoxy-4-hydroxybenzonitrile

2-methoxy-4-hydroxybenzonitrile

2-methoxy-4-hydroxybenzonitrile

4-carbomethoxy-3-hydroxybenzonitrile

5-carbomethoxy-3-hydroxybenzonitrile

3-carbomethoxy-4-hydroxybenzonitrile

2,5-dimethyl-4-hydroxybenzonitrile

3-methyl-4-cyanomethylphenol

2-methyl-4-cyanomethylphenol

2-methyl-3-cyanomethylphenol

4-methyl-3-cyanomethylphenol

5-methyl-3-cyanomethylphenol

2-mercaptobenzonitrile

3-mercaptobenzonitrile

4-mercaptobenzonitrile

3-mercaptobenzylnitrile

4-mercaptobenzylnitrile

4-methyl-3-mercaptobenzonitrile

2-cyanomethyl-1-hydroxymethylbenzene

3-cyanomethyl-1-hydroxymethylbenzene

4-cyanomethyl-1-hydroxymethylbenzene

2-hydroxymethylbenzonitrile

3-hydroxymethylbenzonitrile

4-hydroxymethylbenzonitrile

3-(N-acetylamino)benzonitrile

4-(N-acetylamino)benzonitrile

EXAMPLE 9

When the compounds of Example 6 are used in place of3-(2-quinolinylmethyloxy)benzyl chloride in Examples 7 and 8 then thecorresponding nitriles are obtained.

EXAMPLE 10 5-[3-(3-(2-Quinolinylmethyloxy)benzyloxy)Phenyl]Tetrazole

A mixture of 1.2 g (3.28 mmol) of3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile, 1.89 g (16.4 mmol)of pyridine hydrochloride, and 1.06 g (16.4 mmol) of sodium azide in 10ml of DMF is heated at 100° C. for 4 days. The reaction mixture ispoured into water. The crude product collected on a filter andrecrystallized from ethyl acetate to give5-['-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole. (M.P.169°-172° C.)

EXAMPLE 11

When 4-hydroxybenzyl alcohol is used in place of 3-hydroxybenzyl alcoholin Example 1 and 4-hydroxybenzonitrile is used in place of3-hydroxybenzonitrile in Example 7 then the product obtained is5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole. (M.P.210°-213° C.)

EXAMPLE 12

When 4-cyanomethylphenol is used in place of 4-hydroxybenzonitrile inExample 11 then the product obtained is5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole. (M.P.179°-181° C.)

EXAMPLE 13

When the nitrile compounds of Example 9 are used in place of3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile in Example 10 ofcorresponding tetrazole product is obtained. Representative examples ofcompounds obtained by this invention are shown in Table IV below.

TABLE IV

5-[3-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole

5-[2-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole

5-[4-(2-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole

5-[2-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole

5-[3-(3-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[3-(4-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[2-(3-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[4-(2-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[2-(4-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole

5-[2-(3-(4(2-quinolinylmethyloxy)benzyloxy)phenyl)propyl]tetrazole

5-[2-(3-(4(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl]tetrazole

5-[3-(3-(4(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl]tetrazole

5-[3-(3-(2-quinolinylmethylthio)benzyloxy)phenyl]tetrazole

5-[3-(3-(2-quinolinylmethylthio)benzylthio)phenyl]tetrazole

5-[3-(3-(2-quinolinylmethyloxy)benzylthio)phenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)-3-methoxyphenyl]tetrazole

5-[3-(3-(2-quinolinylmethyloxy)benzyloxy)-4-methoxyphenyl]tetrazole

5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)-3-methoxyphenyl]tetrazole

5-[3-(4-(2-quinolinylmethyloxy)benzyloxy)-4-methoxyphenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)-2-methoxyphenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)-3-carbomethoxyphenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)-3-methoxybenzyl]tetrazole

5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)-3-methoxybenzyl]tetrazole

5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)-3-carbomethoxybenzyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzyloxy)-3-carbomethoxybenzyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)benzylthio)phenyl]tetrazole

5-[3-(4-(2-quinolinylmethyloxy)benzylthio)phenyl]tetrazole

5-[4-(3-(2-quinolinylmethyloxy)-N-acetyl-benzylamino)phenyl]tetrazole

5-[4-(4-(2-quinolinylmethyloxy)-N-acetyl-benzylamino)phenyl]tetrazole

EXAMPLE 14 Methyl3-Methoxy-4-[3-(2-Quinolinylmethyloxy)Benzyloxy]Benzoate

A mixture of 3 g of 3-(2-quinolinylmethyloxy) benzyl chloride, 1.93 g ofmethyl 4-hydroxy-3-methoxy benzoate, and 1.5 g of potassium carbonate in30 ml of DMF is heated at 50° overnight. The reaction mixture is pouredinto water, the solid product collected on a filter and purified by drycolumn chromatography to give methyl3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)-benzoate. (M.P.100°-101° C.)

EXAMPLE 15 3-Methoxy-4-[3-(2-Quinolinylmethyloxy)Benzyloxy]Benzoic Acid

A mixture of 2.6 g of methyl3-methoxy-4-[3-(2-quinolinylmethyloxy)benzyloxy]benzoate and 0.6 g ofNaOH in 15 ml of THF and 2 ml of H2O are heated at 60° C. overnight. Thereaction mixture is diluted with 20 ml of HO and acidified to pH 4. Theproduct is collected on a filter and dried to give3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid. (M.P.188°-190° C.)

EXAMPLE 16

When methyl 4-hydroxy-3-methoxybenzoate is replaced in the procedure ofExample 14 with the compounds of Table V, below, then the correspondingproducts are obtained. Representative examples of compounds prepared bythis invention are shown in Table VI.

TABLE V

methyl 2-hydroxybenzoate

methyl 3-hydroxybenzoate

methyl 4-hydroxybenzoate

methyl 4-hydroxy-3-methoxybenzoate

methyl 3-hydroxy-4-methoxybenzoate

methyl 4-hydroxy-2-methoxybenzoate

methyl 3-hydroxy-4-methoxybenzoate

ethyl 4-hydroxy-3-ethoxybenzoate

methyl 4-hydroxy-3-methylbenzoate

methyl 3-hydroxy-4-methylbenzoate

methyl 4-hydroxy-2-methylbenzoate

methyl 3-hydroxy-4-methylbenzoate

methyl 4-hydroxy-2,6-dimethylbenzoate

methyl 4-hydroxy-2,5-dimethylbenzoate

methyl 2-hydroxyphenylacetate

methyl 3-hydroxyphenylacetate

methyl 4-hydroxyphenylacetate

methyl 4-hydroxyphenylpropionate

methyl 4-hydroxyphenylbutyrate

methyl 4-hydroxyphenyl-3'-methylbutyrate

methyl 4-hydroxy-3-methylphenylacetate

methyl 3-hydroxy-4-methylphenylacetate

methyl 4-hydroxy-3-methoxyphenylacetate

methyl 3-hydroxy-4-methoxyphenylacetate

methyl 2-hydroxymethylbenzoate

methyl 3-hydroxymethylbenzoate

methyl 4-hydroxymethylbenzoate

methyl 2-hydroxymethylphenylacetate

methyl 3-hydroxymethylphenylacetate

methyl 4-hydroxymethylphenylacetate

3-mercaptobenzoate

4-mercaptobenzoate

3-mercaptomethylbenzoate

3-(N-acetylamino)benzoate

4-(N-acetylamino)benzoate

4-(N-benzylamino)benzoate

TABLE VI

4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

4-(4-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

3-(4-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

3-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

2-(4-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

4-(3-(2-quinolinylmethyloxy)benzyloxy)phenylacetic acid

4-(3-(2-quinolinylmethyloxy)phenoxy)benzoic acid

4-(3-(2-quinolinylmethyloxy)benzyloxymethyl)benzoic acid

3-methyl-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

4-methyl-3-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

2-methyl-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

4-methoxy-3-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

2,6-dimethyl-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid

4-(3-(2-quinolinylmethyloxy)benzylthio)benzoic acid

4-(3-(2-quinolinylmethyloxy)benzylamino)benzoic acid

EXAMPLE 17 3-Methoxy-4-(3-(2-Quinolinylmethyloxy)Benzyloxy)Benzoyl-N-Benzenesulfonamide

A reaction mixture of 0.73 g of3-methoxy-4-(3-(2-quinolinyl-methyloxy)benzyloxy)benzoic acid, 0.28 g ofbenzenesulfonamide, 0.28 g of 4-dimethylpyridine, and 0.44 g of1-(3-dimethylamino-propyl)-3-ethylcarbodimide hydrochloride in 50 ml ofCH2Cl2 is stirred at room temperature overnight. The solvent is removedand the residue is extracted into ethyl acetate. The organic solution iswashed with water, and evaporated. The product is purified by dry columnchromatography to give3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoyl-N-benzenesulfonamide.(M.P. 156°-158° C.)

EXAMPLE 18

When 3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid ofExample 17 is replaced by the acids of this invention such as those ofExample 16, Table VI and Example 25, Table IX then the correspondingbenzenesulfonamide compound is prepared.

When benzenesulfonamide is replaced in the above Examples by asulfonamide of the formula NH₂ SO₂ R₃ or an amine of the formulaHN(R₁)₂, then the corresponding product is obtained.

EXAMPLE 19 Methyl 3-(3-(2-Quinolinylmethyloxy)Phenoxymethyl)Benzoate

A mixture of 3-(2-quinolinylmethyloxy)phenol (2.51 g, 0.01 mol), 1.85 g(0.01 mol) of methyl 3-chloromethyl benzoate, and 1.5 g of potassiumcarbonate in 30 ml of DMF is heated at 50° C. overnight. The reactionmixture is poured into water, extracted with ethyl acetate and theorganic solution separated, dried and evaporated to dryness.Recrystallization from ethyl acetate gives methyl3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate. (M.P. 93°-94° C.)

EXAMPLE 20

A mixture of 1.6 g of methyl3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate and 0.5 g of NaOH in20 ml of THF and 5 ml of H2O is heated at 50° C. overnight. The reactionmixture is acidified to pH 4 in 1N HCl solution, filtered and dried togive 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P.149°-151° C.)

EXAMPLE 21

When the procedures of Examples 19 and 20 are followed and methyl3-chloromethylbenzoate is replaced by methyl 4-chloromethylbenzoate,then the product prepared is4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P. 190°-191°C.)

EXAMPLE 22

When the procedures of Examples 19 and 20 are followed and methyl3-chloromethylbenzoate is replaced by methyl3-methoxy-4-chloromethylbenzoate then the product prepared is3-methoxy-4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P.208°-210° C.)

EXAMPLE 23

When the procedure of Example 19 is followed and the compounds of TableVII below are used in place of methyl 3-chloromethyl-benzoate then thecorresponding product is obtained.

TABLE VII

ethyl 2-chloromethylbenzoate

ethyl 3-chloromethylbenzoate

ethyl 4-chloromethylbenzoate

ethyl 3-chloromethylbenzoate

methyl 4-chloromethylbenzoate

methyl 2-methyl-5-chloromethylbenzoate

methyl 2-methyl-3-chloromethylbenzoate

methyl 3-methyl-5-chloromethylbenzoate

methyl 4-methyl-5-chloromethylbenzoate

methyl 2-methyl-4-chloromethylbenzoate

methyl 3-methyl-4-chloromethylbenzoate

methyl 2-methoxy-5-chloromethylbenzoate

methyl 2-methoxy-3-chloromethylbenzoate

methyl 2-methoxy-4-chloromethylbenzoate

methyl 3-methoxy-4-chloromethylbenzoate

methyl 3-chloromethylphenylacetate

methyl 4-chloromethylphenylacetate

methyl 3-chloromethylphenylpropionate

methyl 4-chloromethylphenylpropionate

methyl 3-chloromethylphenylbutyrate

methyl 4-chloromethylphenylbutyrate

methyl 3-chloromethylphenylisopropionate

methyl 4-chloromethylphenylisopropionate

methyl 3-chloromethylphenylisopropionate

methyl 4-chloromethylphenylisobutyrate

EXAMPLE 24

When the procedure of Example 19 is followed and the compound of TableVIII below are used in place of 3-(2-quinolinyl-methyloxy)phenol thenthe corresponding product is obtained.

TABLE VIII

3-(2-quinolinylmethyloxy)phenol

4-(2-quinolinylmethyloxy)phenol

3-(2-quinolinylmethylthio)phenol

4-(2-quinolinylmethylthio)phenol

5-methyl-3(2-quinolinylmethyloxy)phenol

2-methyl-3(2-quinolinylmethyloxy)phenol

5-methyoxy-3(2-quinolinylmethyloxy)phenol

2-methyl-4-(2-quinolinylmethyloxy)phenol

2-methoxy-4-(2-quinolinylmethyloxy)phenol

3-methoxy-4-(2-quinolinylmethyloxy)phenol

3-methyl-4-(2-quinolinylmethyloxy)phenol

3-(2-quinolinylmethyloxy)phenol mercaptan

4-(quinolinylmethyloxy)phenol mercaptan

3-(2-quinolinylmethylthio)phenyl mercaptan

4-(2-quinolinylmethylthio)phenol mercaptan

N-benzyl-3-(2-quinolinylmethyloxy)phenylamine

N-methyl-3-(2-quinolinylmethyloxy)phenylamine

N-acetyl-3-(2-quinolinylmethyloxy)phenylamine

N-acetyl-4-(2-quinolinylmethyloxy)phenylamine

EXAMPLE 25

When the procedures of Examples 19 and 20 are followed using thecompounds of Table VII, Example 23 and Table VIII, Example 24, then thecorresponding product is obtained. Representative examples of compoundsprepared by this invention are shown in Table IX.

TABLE IX

3-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

4-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-methyl-3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-ethyl-3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-methoxy-3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

3-methyl-4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-methyl-4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

2-methoxy-4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid

3-(3-(2-quinolinylmethyloxy)-5-methylphenoxymethyl)benzoic acid

3-(3-(2-quinolinylmethyloxy)-5-methoxyphenoxymethyl)benzoic acid

3-(4-(2-quinolinylmethyloxy)-3-methylphenoxymethyl)benzoic acid

3-(4-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)benzoic acid

2-methyl-3-(3-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)benzoic acid

3-(3-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid

4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid

3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenylacetic acid

3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenylpropionic acid

3-(3-(2-quinolinylmethyloxy)phenylthiomethyl)benzoic acid

4-(3-(2-quinolinylmethyloxy)phenylthiomethyl)benzoic acid

3-(4-(2-quinolinylmethyloxy)phenylthiomethyl)benzoic acid

3-(3-(2-quinolinylmethyloxy)phenyl-N-acetylamino-methyl)benzoic acid

4-(4-(2-quinolinylmethyloxy)phenyl-N-acetylaminomethyl)benzoic acid

EXAMPLE 26 4-(3-(2-Quinolinylmethyloxy)Phenoxymethyl)Benzonitrile

A solution of 7.24 g (19.92 mmol) of sodium3-(2-quinolinylmethyloxy)phenoxide pentahydrate and 4.68 g (23.90 mmol)of p-cyanobenzyl bromide in 34 ml of dry DMF is stirred at 75° C. undernitrogen for 2 days. The reaction mixture is cooled to room temperature,then poured into 400 ml of 3:1 H₂ O/Et₂ O, shaken, and the phasesseparated. The aqueous layer is extracted and washed with 1:1 brine/H₂ Oand brine. The ether solution is dried over 1:1 Na₂ SO₄ MgSO₄, filteredand concentrated. The crude product is recrystallized from 70%EtOAc/hexane to obtain4-(3-(2-quinolinylmethyloxy)phenoxy-methyl)benzonitrile. (M.P. 112.5°C.)

EXAMPLE 27 5-(4-(3-(2-Quinolinylmethyloxy)Phenoxymethyl)Phenyl)Tetrazole

A slurry of 2.0 g (5.48 mmol) of4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzonitrile, 1.78 g (27.4mmol) of sodium azide, and 3,16 g (27.4 mmol) of pyridiniumhydrochloride in 12 ml of dry DMF is stirred under nitrogen at 100° C.for 20 hrs. The reaction mixture is then cooled to room temperature andconcentrated. The residue is taken up on 100 ml of 1N aqueous NaOH andthe solution extracted with ether. The aqueous layer is acidified to pH6 with 1N aqueous HCl, and the precipitate collected, triturated withwater, filtered and lyophilized to obtain5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P. 91°C. dec.)

EXAMPLE 28

When the procedures of Examples 26 and 27 are followed and p-cyanobenzylbromide is replaced by o-cyanobenzyl bromide, m-cyanobenzyl bromide,o-(cyanomethyl)benzyl bromide, m-(cyanomethyl)benzyl bromide,p-(cyanomethyl)-benzyl bromide, then the products prepared are:

5-(2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P.166°-170° C.);

5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P. 115°C. dec.);

5-(2-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole (M.P.145.5°-147° C.);

5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole (M.P.161°-164° C.); and

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole (M.P.149°-152° C.).

EXAMPLE 29

When the procedure of Example 26 is followed and the compounds of TableX below are used in place of p-cyanobenzyl bromide then thecorresponding product is obtained.

TABLE X

2-methyl-4-cyanobenzyl bromide

3-methyl-4-cyanobenzyl bromide

3-methoxy-2-cyanobenzyl bromide

2-methyl-3-cyanobenzyl bromide

3-cyano-4-methylbenzyl bromide

4-methoxy-2-cyanobenzyl bromide

3-cyano-5-methylbenzyl bromide

2-methyl-5-cyanobenzyl bromide

2-methoxy-5-cyanobenzyl bromide

2-methoxy-4-cyanobenzyl bromide

2-methoxy-3-cyanobenzyl bromide

2,6-dimethyl-4-cyanobenzyl bromide

3-methoxy-4-cyanobenzyl bromide

2-methyl-6-cyanobenzyl bromide

o-cyanobenzyl bromide

m-cyanobenzyl bromide

p-cyanobenzyl bromide

2-cyanomethylbenzyl bromide

3-cyanomethylbenzyl bromide

4-cyanomethylbenzyl bromide

3-(1'-cyanoethyl)benzyl bromide

3-(2'-cyanoethyl)benzyl bromide

4-(1'-cyanoethyl)benzyl bromide

4-(2'-cyanoethyl)benzyl bromide

3-(1'-cyanopropyl)benzyl bromide

3-(2'-cyanopropyl)benzyl bromide

3-(3'-cyanopropyl)benzyl bromide

4-(1'-cyanopropyl)benzyl bromide

4-(2'-cyanopropyl)benzyl bromide

4-(3'-cyanopropyl)benzyl bromide

3-(1'-cyanobutyl)benzyl bromide

3-(2'-cyanobutyl)benzyl bromide

3-(3'-cyanobutyl)benzyl bromide

3-(4'-cyanobutyl)benzyl bromide

4-(1'-cyanobutyl)benzyl bromide

4-(2'-cyanobutyl)benzyl bromide

4-(3'-cyanobutyl)benzyl bromide

4-(4'-cyanobutyl)benzyl bromide

3-(2'-methyl-1'-cyanobutyl)benzyl bromide

3-(3'-methyl-1'-cyanobutyl)benzyl bromide

4-(2'-methyl-1'-cyanobutyl)benzyl bromide

4-(3'-methyl-1'-cyanobutyl)benzyl bromide

EXAMPLE 30

When the procedure of Example 26 is followed and the sodium or otherappropriate salt of the alcohol or mercaptan of Table VIII, Example 24is used is place of sodium 3-(2-quinolinylmethyloxy)-phenoxide then thecorresponding product is obtained.

EXAMPLE 31

When the procedures of Examples 26 and 27 are followed using thecompounds of Table X, Examples 29 and the appropriate alcohol, thio oramino salt formed in Example 30, then the corresponding products areobtained. Representative examples of compounds prepared by thisinvention are shown in Table XI.

TABLE XI

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(3-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(2-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(4-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(2-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl) tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-5-methoxyphenoxymethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-5-methylphenoxymethyl)phenyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)phenyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)-2-methoxyphenoxymethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)phenyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)phenyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-3-methylphenoxymethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethylthio)phenoxymethyl)phenyl)tetrazole

5-(3-(3-(2-quinolinylmethylthio)phenoxymethyl)phenyl)tetrazole

5-(2-(3-(2-quinolinylmethylthio)phenoxymethyl)phenyl)tetrazole

5-(2-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenethyl)tetrazole

5-(3-(2(4-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)propyl)tetrazole

5-(4-(3(2-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)butyl)tetrazole

5-(2-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)propyl)tetrazole

5-(3-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)butyl)tetrazole

5-(4-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)-3methylbutyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenylthiomethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethylthio)phenylthiomethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-3-methylphenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-2-methylphenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-2-methoxyphenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-3-methoxyphenyl)tetrazole

5-(2-(4-(2-quinolinylmethyloxy)phenoxymethyl)-3-methylphenyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)-4-methoxyphenyl)tetrazole

5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)-4-methoxyphenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-5-methylphenoxymethyl)-2-methoxyphenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-N-acetylphenylaminomethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethylthio)-N-acetylphenylaminomethyl)phenyl)tetrazole

EXAMPLE 325-(3-(4-(2-Quinolinylmethyloxy)Phenoxymethyl)Phenoxymethyl)Tetrazole A.α-(3-hydroxymethylphenoxy)acetonitrile

A mixture of 3-hydroxymethyl phenol (0.081 mol), bromacetonitrile (0.081mol) and anhydrous potassium carbonate (0.081 mol) in acetone (160 ml)and dimethylformamide (20 ml) are heated at reflux for 48 hrs. Thereaction mixture is filtered and evaporated. The residue is diluted withethyl acetate (150 ml), washed with 10% aqueous sodium hydroxidesolution (3×100 ml) and then with brine (3×100 ml). The ethyl acetatesolution is dried (magnesium sulfate) and chromatographed using a silicagel column (ca. 100 g) and eluted with 1:1 petroleum ether: ethylacetate(2l). The resultant oil is used directly in the next step.

B. α-(3-chloromethylphenoxy)acetonitrile

α-(3-Hydroxymethylphenoxy)acetonitrile (0.055 mol) in diethylether (150ml) is stirred with thionyl chloride (0.060 mol) and a few drops ofdimethylformamide at 40° C. for 1 hr. the solution is washed with waterand brine, then evaporated to give α-(3-chloromethylphenoxy)acetonitrileas a yellow oil which is used directly in the next step.

C. α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy) acetonitrile

A mixture of α-(3-chloromethylphenoxy)acetonitrile (0.025 mol), sodium4-(2-quinolinylmethyloxy)phenoxide (0.025 mol and anhydrous potassiumcarbonate (0.125 mol) in dimethylsulfoxide (50 ml) is stirred at ambienttemperature for 18 hrs. The reaction is diluted with water (600 ml) andextracted with ethyl acetate (3×150 ml). The ethyl acetate solution iswashed with water (3×100 ml) and brine (100 ml) then dried andevaporated to giveα-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile. (M.P.110°-114° C.)

D. 5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile (8.12mmol), sodium azide (24.4 mmol) and ammonium chloride (24.4 mmol) indimethylformamide (10 ml) are heated at 115°-120° C. for 6 hrs. Aftercooling, the reaction mixture is diluted with ethyl acetate (150 ml),washed with water (6×100 ml) then dried and evaporated. The residue ischromatographed on a column of silica gel (360 g) and eluted with agradient of isopropanol in methylene chloride to give5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole(M.P. 131°-132° C.)

EXAMPLE 33

When sodium 4-(2-quinolinylmethyloxy)phenoxide of Example 32, Step C, isreplaced with sodium 3-(2-quinolinylmethyloxy)phenoxide, the productprepared is5-(3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole.(M.P. 135°-137° C.)

EXAMPLE 34

When α(3-hydroxymethylphenoxy)acetonitrile of Example 33, Step B, isreplaced with α(4-hydroxymethylphenoxy)acetonitrile then the produceprepared is5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole.(M.P. 154°-156° C.)

EXAMPLE 35

When α(3-hydroxymethylphenoxy)acetonitrile of Example 33, Step B, isreplaced with α(2-hydroxymethylphenoxy)acetonitrile orα[(2-hydroxymethyl-5-carbomethoxy)phenoxy)acetonitrile then the productsprepared are5-(2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole(M.P. 118°-120° C.) or5-(2-(3-(2-quinolinylmethyloxy)phenoxymethyl)-5-carbomethoxy-phenoxymethyl)tetrazole.(M.P. 159°-162° C.)

EXAMPLE 36

When bromoacetronitrile of Example 32, Step A is replaced by thenitriles of Table XIII below then the corresponding product is prepared:

TABLE XII

bromoacetonitrile

α-bromo-α-methylacetonitrile

α-bromo-β-ethylacetonitrile

α-bromopropionitrile

β-bromopropionitrile

β-bromo-β-methylpropionitrile -bromobutyronitrile

β-bromobutyronitrile

α-bromobutyronitrile

EXAMPLE 37

When 3-hydroxymethylphenol of Example 32, Step A is replaced by thecompounds of Table XIII below, then the corresponding products areprepared.

TABLE XIII

2-hydroxymethylphenol

3-hydroxymethylphenol

4-hydroxymethylphenol

3-mercaptobenzylalcohol

4-mercaptobenzylalcohol

3-hydroxymethyl-N-acetylamidine

4-hydroxymethyl-N-acetylamidine

4-hydroxymethylamidine

4-methyl-2-hydroxymethylphenol

2-methyl-5-hydroxymethylphenol

4-methyl-3-hydroxymethylphenol

5-methyl-3-hydroxymethylphenol

3-methyl-4-hydroxymethylphenol

2-methyl-4-hydroxymethylphenol

3-methyl-5-hydroxymethylphenol

4-methoxy-3-hydroxymethylphenol

3-methoxy-4-hydroxymethylphenol

2-methoxy-4-hydroxymethylphenol

5-methoxy-3-hydroxymethylphenol

3-methoxy-5-hydroxymethylphenol

2-methoxy-5-hydroxymethylphenol

2-(1'-hydroxyethyl)phenol

3-(1'-hydroxyethyl)phenol

4-(1'-hydroxyethyl)phenol

2-(2'-hydroxyethyl)phenol

3-(2'-hydroxyethyl)phenol

4-(2'-hydroxyethyl)phenol

2-(3'-hydroxypropyl)phenol

3-(3'-hydroxypropyl)phenol

4-(3'-hydroxypropyl)phenol

2-(2'-hydroxypropyl)phenol

3-(2'-hydroxypropyl)phenol

4-(2'-hydroxypropyl)phenol

2-(1'-hydroxypropyl)phenol

3-(1'-hydroxypropyl)phenol

4-(1'-hydroxypropyl)phenol

3-(4'-hydroxybutyl)phenol

4-(4'-hydroxybutyl)phenol

EXAMPLE 38

Following the procedures of Examples 32 to 34, when sodium4-(2-quinolinylmethyloxy)phenoxide of Example 32, Step C, is replaced bythe metal hydroxy, thio or amino salts of the compounds of Table VIII,Example 24, then the corresponding product is prepared. Representativeexamples of compounds prepared by this invention are shown in TableXIII.

TABLE XIII

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(4-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(3-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(2-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(2-(2-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)-2-methoxyphenoxymethyl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)-3-methoxyphenoxymethyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-2-methoxyphenoxymethyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-3-methoxyphenoxymethyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-3-methylphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)-2-methoxyphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)-3-methoxyphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)-3-methylphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)phenoxymethyl)-2-methylphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)phenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-3-methylphenoxymethyl)phenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-3-methoxyphenoxymethyl)phenoxymethyl)tetrazole

5-(3-(3-(2-quinolinylmethyloxy)-4-methoxyphenoxymethyl)phenoxymethyl)tetrazole

5-(3-(3-(2-quinolinylmethyloxy)-4-methoxyphenoxymethyl)phenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-2-methylphenoxymethyl)-3-methylphenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-3-methylphenoxymethyl)-2-methylphenoxymethyl)tetrazole

5-(2-(3-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenoxy)ethyl)tetrazole

5-(3-(3-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenoxy)propyl)tetrazole

5-(2-(3-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenoxy)propyl)tetrazole

5-(3-(3-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenoxy)butyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-phenythiomethyl)phenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-phenythiomethyl)phenylthiomethyl)tetrazole

5-(4-(4-(2-quinolinylmethylthio)-phenoxymethyl)phenoxymethyl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenyl-N-acetylaminomethyl)tetrazole

5-(3-(4-(4-(2-quinolinylmethyloxy)-phenoxymethyl)phenylthio)butyl)tetrazole

5-(3-(3-(4-(2-quinolinylmethyloxy)phenoxy-1'-ethyl)phenoxymethyl)tetrazole

5-(3-(3-(4-(2-quinolinylmethyloxy)phenoxy-2'-propyl)phenoxymethyl)tetrazole

5-(3-(3-(4-(2-quinolinylmethyloxy)phenoxy-3'-butyl)phenoxymethyl)tetrazole

EXAMPLE 39 3-(3-(2-Quinolinylmethyloxy)Benzyloxy)Benzaldehyde

When 3-hydroxybenzonitrile in Example 7 is replaced by3-hydroxybenzaldehyde then the product prepared is3-[3-(2-quinolinylmethyloxy)benzyloxy)benzaldehyde.

EXAMPLE 40 When 3-hydroxybenzaldehyde of Example 39 is replaced by thecompounds of Table XIV below, then the corresponding product isobtained. TABLE XIV

2-hydroxybenzaldehyde

3-hydroxybenzaldehyde

4-hydroxybenzaldehyde

2-methyl-3-hydroxybenzaldehyde

5-methyl-3-hydroxybenzaldehyde

2-methyl-4-hydroxybenzaldehyde

3-methyl-4-hydroxybenzaldehyde

5-methoxy-3-hydroxybenzaldehyde

4-methoxy-3-hydroxybenzaldehyde

2-methoxy-3-hydroxybenzaldehyde

5-carbomethoxy-3-hydroxybenzaldehyde

3-hydroxyphenylacetaldehyde

4-hydroxyphenylacetaldehyde

3-hydroxyphenylpropionaldehyde

4-hydroxyphenylpropionaldehyde

3-hydroxyphenylisopropionaldehyde

4-hydroxyphenylisopropionaldehyde

3-hydroxyphenoxyacetaldehyde

4-hydroxyphenylthiopropionaldehyde

EXAMPLE 41

When 3-2-quinolinylmethyloxy)benzyl chloride of Example 39 is replacedby the compounds prepared by Examples 2-6 and 3-hydroxybenzaldehyde ofExample 39 is replaced by the compounds of Table XIV, Example 40, thenthe corresponding products are obtained.

EXAMPLE 42 3-(3-(2-Quinolinylmethyloxy)Benzyloxy)Cinnamylnitrile

Sodium hydride (60% oil dispersion, 1.2 g) and diethylcyanomethylphosphonate (5 ml) are combined and stirred in THF (50 ml)for 5 minutes. This is then added to a THF solution of3-(3-(2-quinolinylmethyloxy)benzyloxy)benzaldehyde (9.59 g). Thereaction mixture is stirred for an additional 30 minutes and poured intoice water. The crude product is filtered and chromatographed through asilica gel dry column using chloroform as the eluant to give3-(3-(2-quinolinylmethyloxy)benzyloxy)cinnamylnitrile.

EXAMPLE 43

When 3-(3-(2-quinolinylmethyloxy)benzyloxy)benzaldehyde of Example 42 isreplaced by the compounds of Example 41, the corresponding product isprepared.

When diethylcyanomethylphosphonate in the above Example is replaced bydiethylcyanoethylphosphate, diethylcyanopropylphospate ordiethylcyanoisopropylphosphate then the corresponding products areobtained.

EXAMPLE 44 5-(3-(3-(2-Quinolinylmethyloxy)Benzyloxy)StyryltetrazoleHydrochloride

A mixture of 3-(3-(2-quinolinylmethyloxy)benzyloxy)cinnamylnitrile (0.03mol), anhydrous aluminum chloride (0.03 mol) and sodium azide (0.09 mol)in THF (30 ml) is stirred and refluxed for 18 hours. Hydrochloric acid(18% HCl 15 ml) is added and thereafter the reaction mixture is pouredinto ice water. The precipitate is collected and then recrystallizedfrom methanol-ethyl acetate to obtain pure5-(3-(3-(2-quinolinylmethyloxy)benzyloxy)styryl)tetrazole hydrochloride.

The free base is obtained by treatment of the salt with one equivalentof sodium hydroxide solution followed by removal of sodium chloride andwater.

EXAMPLE 45

When (3-(3-(2-quinolinylmethyloxy)benzyloxy)cinnamylnitrile of Example44 is replaced by the compounds formed in Example 43, then thecorresponding product is prepared. Representative compounds prepared bythis invention are described in Table XV.

TABLE XV

5-(4-(3-(2-quinolinylmethyloxy)phenoxy)styryl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)benzyloxy)styryl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)benzyloxy)styryl)tetrazole

5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)styryl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)-4-methylbenzyloxy)styryl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)benzyloxy)3-methylstyryl)tetrazole

5-(3-(3-(2-quinolinylmethylthio)benzyloxy)styryl)tetrazole

5-(3-(4-(2-quinolinylmethylthio)phenoxy)styryl)tetrazole

5-(3-(4-(2-quinolinylmethyloxy)benzylthio)styryl)tetrazole

5-(3-(4-(3-(2-quinolinylmethyloxy)benzyloxy)phenoxy)2-propen-1-yl)tetrazole

EXAMPLE 463-Methylcarboethoxy-5-(4-(3-(2-Quinolinylmethyloxy)Phenoxymethyl)Phenyl)Tetrazole

To a solution of 0.2 g sodium in 30 ml ethanol is first added 1 g of5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole and thenafter 30 minutes 0.6 g of ethylbromoacetate and stirring is continued at80° C. for 16 hours. The solvent is then removed, diluted with water,filtered, washed with ether and dried to give the desired compound, alsoreferred to as ethyl5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole-3-ylacetate.

When ethylbromoacetate in the above procedure is replaced withN,N-diethyl-α-bromoacetamide, N,N-diethyl-aminoethyl bromide orN-acetylaminoethyl bromide or N-acetyl-α-bromoacetamide, then thecorresponding products are obtained.

EXAMPLE 475-(4-(3-(2-Quinolinylmethyloxy)Phenoxymethyl)Phenyl)Tetrazol-3-Yl)Acetic Acid

A mixture of 1 g of ethyl[5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazol-3-yl]acetate in 5 ml ethanol and 40 ml of 1N NaOH is stirred at 70° C. for 4hours. This is cooled, diluted with water, acidified with acetic acid,filtered, washed with water, and then ethyl acetate to give5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazol-3-yl aceticacid.

In a similar manner, the substituted tetrazoles of this invention may beprepared.

EXAMPLE 48 4-(4-(2-Quinolinylmethylsulfonyl)Phenoxymethyl)Benzoic Acid

A. 4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) indichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol)and solid potassium hydrogen carbonate (1.0 g). The reaction is assayedby TLC and upon consumption of the starting thio compound, the mixtureis filtered, washed with dilute aqueous sodium bisulfite, dried andevaporated to give4-(4-(2-quinolinylmethylsulfinyl)phenoxymethyl)benzoic acid.

B. To 3 mmol of the sulfinyl compound from Step A in acetic acid (40mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred atambient temperature and assayed by TLC. Upon disappearance of thesulfinyl starting compound, the reaction mixture is diluted withdichloromethane, washed with dilute aqueous sodium bisulfite and water,dried and evaporated to give4-(4-(2-quinolinylmethylsulfonyl)phenoxymethyl)benzoic acid.

In a similar manner, the sulfinyl and sulfonyl compounds of thisinvention may be prepared.

EXAMPLE 495-(3-Methyl-4-(4-(4-(2-Quinolinylmethyloxy)Benzyloxy)Phenyl)Butyl)Tetrazole

A. 4-benzyloxy-α-methyl-cinnamic acid ethyl ester. To a solution ofsodium hydride (60% oil dispersion, 3.1 g) and diethyl2-phosphonopropionate (15.5 g) in tetrahydrofuran (50 ml) is addeddropwise a tetrahydrofuran solution of 4-benzyloxy-benzaldehyde (10.6g). After stirring at room temperature for 2 hours, the reaction mixtureis poured into ice water. The insoluble solid is collected, and useddirectly in the next step.

B. 4-benzyloxy-α-methyl-cinnamic alcohol. Under argon and with stirring,a tetrahydrofuran solution of 4-benzyloxy-α-methyl-cinnamic acid ethylester (11.9 g) is added dropwise to a cooled tetrahydrofuran solution oflithium aluminum hydride (2.5 g). The reaction mixture is allowed tostir for 18 hours and afterward, the excess reagent is destroyed in aconventional manner. The residue which results from the evaporation ofthe solvent is partitioned in a water/ethyl acetate mixture and from theorganic layer, the desired product is obtained. This is used directly inthe next step.

C. 4-benzyloxy-α-methyl-cinnamyl aldehyde. Manganese dioxide (15 gtotal) is added portionwise to a dichloromethane solution (100 ml) of4-benzyloxymethylcinnamic alcohol with stirring over a period of oneweek. After two filtrations, the filtrate is evaporated to yield a gum.Upon treatment with cold hexane, the crude product results which is useddirectly in the next step.

D. 5-(p-benzyloxyphenyl)-4-methyl-2,4-pentadienenitrile. To a solutionof sodium hydride (60% oil dispersion, 1.5 g) and diethylcyanomethylphosphonate (5.4 g) in tetrahydrofuran (50 ml) is addeddropwise a tetrahydrofuran solution of 4-benzyloxy-α-methyl-cinnamylaldehyde (4.8 g). After stirring at room temperature for 2 hours, thereaction mixture is poured into ice water. The insoluble material iscollected and used directly in the next step.

E. 5-(p-hydroxyphenyl-4-methylvaleronitrile.5-(p-Benzyloxyphenyl)-4-methyl-2,4-pentadienenitrile (4.3 g) dissolvedin ethanol is hydrogenated (0.8 g of 5% palladium over charcoal ascatalyst) around 30 psi overnight. After filtering off the catalyst, thesolvent is evaporated to give an oil which is used directly in the nextstep.

F.4-methyl-5-(4-(4-(2-quinolinyloxymethyl)benzyloxy)phenyl)valeronitrile.A reaction mixture of 5-p-hydroxyphenyl-4-methyl-valeronitrile (2.9 g),4-(2-quinolinylmethyloxy)benzyl chloride hydrochloride (6.3 g) andanhydrous potassium carbonate (30 g) in dimethylformamide (60 ml) isstirred and heated (110° C.) for 5 hours. Afterward, the solvent isremoved under vacuum and the residue is partitioned in a mixture ofchloroform/water. The organic layer is evaporated and the resultant oilis purified on a silica gel dry column (chloroform as eluant) to giveproduct which may used directly in the next step.

G. 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)phenyl)butyl)tetrazole. Amixture of 4-methyl-5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl)valeronitrile (1.5 g.), sodium aside (3 g), ammonium chloride (1.9 g) indimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours.After cooling, the reaction mixture is poured into ice water and theinsoluble material is taken up by chloroform. The residue from theevaporation of chloroform is purified by silica gel dry column (5%methanol in chloroform as eluant) to yield5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.

EXAMPLE 50

When 2-chlormethylquinoline of Example 49, Part F is replaced by thequinoline compounds of Examples 5 and 6, then the corresponding productis obtained. When the products are treated according to the proceduresof Steps F and G, then the corresponding tetrazole products areobtained.

EXAMPLE 51

When diethyl 2-phosponopropionate of Example 49, Step A is replaced bythe Wittig reagents of Table XVI below then the corresponding productsare obtained.

TABLE XVI

diethyl 2-phosphonoacetate

diethyl 2-phosphonopriopionate

diethyl 3-phosphonopropionate

diethyl 4-phosphonobutyrate

diethyl 3-phosphonobutyrate

diethyl 2-phosphonobutyrate

diethyl 5-phosphonopentanoate

diethyl 4-phosphonopentanoate

diethyl 3-phosphonopentanoate

diethyl 4-phosphono-3-methylbutyrate

diethyl 4-phosphono-2,3-dimethylbutyrate

diethyl 5-phosphono-4-methylpentanoate

diethyl 5-phosphono-3,4-dimethylpentanoate

diethyl 4-phosphono-3,3-dimethylbutyrate

diethyl 4-phosphono-3-phenylbutyrate

diethyl 4-phosphono-3-benzylbutyrate

diethyl 3-phosphono-2,2-dimethylpropionate

diethyl 4-phosphono-2-propylbutyrate

diethyl 4-phosphono-3-propylbutyrate

diethyl 3-phosphonomethylhexanoate

diethyl 4-phosphonoheptanoate

EXAMPLE 52

When diethylcyanomethylphosphonate of Example 49, Step D is replaced bythe Wittig reagents of Table XVII below then the corresponding productsare obtained.

TABLE XVII

diethyl 2-phosphonoacetonitrile

diethyl 3-phosphonopropionitrile

diethyl 2-phosphonopropionitrile

diethyl 4-phosphonobutyronitrile

diethyl 3-phosphonobutyronitrile

diethyl 2-phosphonobutyronitrile

diethyl 5-phosphonopentanonitrile

diethyl 4-phosphonopentanonitrile

diethyl 3-phosphonopentanonitrile

diethyl 2-phosphonopentanonitrile

diethyl 4-phosphono-5-phenylpentanonitrile

diethyl 4-phosphono-3-phenylbutyronitrile

diethyl 4-phosphono-5-cyclopropylpentanonitrile

diethyl 4-phosphonohexanonitrile

diethyl 4-phosphonoheptanonitrile

diethyl 4-phosphono-5-carbethoxypentanonitrile

diethyl 4-phosphono-3-methylenebutyronitrile

diethyl 4-phosphono-3-ethylidenebutyronitrile

diethyl 1-phosphonomethyl-1-cyanoethylcyclopropane

diethyl 1-phosphonomethyl-1-cyanomethylcyclobutane

diethyl 1-phosphonomethyl-2-cyanomethylcyclobutane

diethyl 1-phosphonomethyl-2-cyanomethylcyclopentane

EXAMPLE 53

When diethyl 2-phosphonopropionate of Example 49, Step A is replaced bythe Wittig reagents of Table XVII, Example 52, then the correspondingproducts are obtained. When these products are then treated according tothe procedure of Example 50, then the corresponding product is obtained.

EXAMPLE 54

When 4-hydroxy-3-methoxybenzoate of Example 14 is replaced with3-hydroxymethylphenol, then the product prepared is3-(3-(2-quinolinylmethyloxy)benzyloxy)benzyl alcohol.

EXAMPLE 55

When 4-hydroxy-3-methoxybenzoate of Example 14 is replaced with thecompounds of Table XVIII below and 3-(2-quinolinylmethyloxy)benzylchloride is replaced by the compounds of Example 6, then thecorresponding products are prepared.

TABLE XVIII

1,2-dihydroxybenzene

1,3-dihydroxybenzene

1,4-dihydroxybenzene

2-mercaptophenol

3-mercaptophenol

4-mercaptophenol

1,3-dimercaptobenzene

3-hydroxymethylphenol

3-hydroxyethylphenol

3-mercaptomethylphenol

4-hydroxymethylphenol

4-hydroxyethylphenol

2-methylresorsinol

5-methylresorsinol

5-methyl-1,4-dihydroxybenzene

EXAMPLE 56 5-(3-Chloropropyl)Tetrazole

A mixture of 3.5 g of 4-chlorobutyronitrile, 2.3 g of sodium azide and1.9 g of ammonium chloride in 50 ml of dimethyl-formamide is stirred at140° C. for 20 hours. The reaction mixture is poured onto ice, basifiedwith 1N sodium hydroxide and extracted twice with ethyl acetate. Theaqueous fraction is acidified with acetic acid and extracted withethylacetate. Evaporation of the ethyl acetate gives5-(3-chloropropyl)-tetrazole which is used directly in the next step.

EXAMPLE 57

When 4-chlorobutyronitrile of Example 56 above is replaced by thenitriles of Table XIX below then the corresponding tetrazole product isobtained.

TABLE XIX

chloracetonitrile

bromoacetonitrile

3-chloropropionitrile

4-chlorobutyronitrile

5-chloropentanonitrile

6-chlorohexanonitrile

2-chloropropionitrile

2-methyl-3-chloropropionitrile

2-chlorobutyronitrile

3-chlorobutyronitrile

4-methyl-5-chloropentanonitrile

2-methyl-3-chloropropinonitrile

3-benzyl-4-chlorobutyronitrile

3-carbethoxymethyl-4-chlorobutyronitrile

3-methoxymethyl-4-chlorobutyronitrile

2,3-dimethyl-4-chloropentanonitrile

3,3-dimethyl-4-chloropentanonitrile

spiro-(3,3-cyclopropane)4-chlorobutyronitrile

1-chloromethyl-2-cyanomethylcyclobutane

1-chloromethyl-2-cyanomethylcyclohexane

3-cyclopropylmethyl-4-chlorobutyronitrile

3-dimethylaminomethyl-4-chlorobutyronitrile

3-methylene-4-chlorobutyronitrile

3-propylidene-4-chlorobutyronitrile

EXAMPLE 585-(4-(3-(3-(2-Quinolinylmethyloxy)Benzyloxy)Phenyl)Butyl)Tetrazole

A mixture of (0.014 mol) 3-(3-(2-quinolinylmethyloxy)benzyloxy)benzylalcohol (0.14 mol) 5-(3-chloropropyl)tetrazole and 2 g (0.036 mol KOH in5 ml water and 50 ml ethanol is heated over a steam bath for a period of3 hours. Reaction mixture is concentrated to dryness and slurried intowater and extracted with methylene chloride. The methylene chlorideextract is washed with water, dried over MgSO₄ and concentrated underreduced pressure to obtain solid which is passed through a silica gelcolumn using hexane/ethyl acetate as eluent. Evaporation of eluent gives5-(4-(3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole.

EXAMPLE 59

When 3-(3-(2-quinolinylmethyloxy)benzyloxy)benzyl alcohol of Example 58is replaced by the compounds prepared by Examples 54 and 55 and5-(3-chloropropyl)tetrazole is replaced by the compounds prepared byExample 57, then the corresponding product is obtained.

TABLE XX

5-(4-(4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole

5-(3-(4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole

5-(3-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole

5-(2-(3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)propyl)tetrazole

5-(3-(3-(3-(2-quinolinylmethylthio)benzyloxy)phenyl)butyl)tetrazole

5-(3-(3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole

5-(3-(3-(3-(2-quinolinylmethyloxy)benzylthio)phenyl)butyl)tetrazole

5-(4-(3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)butyl)tetrazole

5-(3-(3-(3-(2-quinolinylmethyloxy)phenoxy)phenyl)butyl)tetrazole

EXAMPLE 60

When 3-hydroxybenzonitrile in Example 7 is replaced by3-hydroxybenzaldehyde then the product prepared is3-(2-quinolinylmethyloxy)benzaldehyde.

EXAMPLE 61

When 3-hydroxybenzaldehyde in Example 60 is replaced by the compounds ofTable XIV, Example 40 and 3-(2-quinolinylmethyloxy)benzyl chloride isreplaced by the chlorides prepared in Examples 5 and 6, then thecorresponding product is prepared.

EXAMPLE 62 5-(4-(3-(2-Quinolinylmethyloxy)Benzoylmethyl)Phenyl)Tetrazole

A. 2-(3-(2-quinolinylmethyloxy)phenyl)-1,3-dithiane. A 1M solution of3-(2-quinolinylmethyloxy)benzaldehyde (0.01 mol) in chloroform iscombined with an equimolar amount of 1,3 propane-dithiol at -20° C. DryHCl gas is slowly passed through the solution for 5-10 minutes. Thereaction mixture is then allowed to come to room temperature. After 3hours, the reaction mixture is worked up by successively washing withwater, 10% aqueous KOH and water and drying over K₂ CO₃. Evaporation ofthe solvent furnishes the desired product which is purified by columnchromatography to give product which is used directly in the next step.

B. 2-(3-(2-quinolinylmethyloxy)phenyl-2-(p-cyanobenzyl)-1,3-dithiane. Toa 0.2M THF solution of the2-(3-(2-quinolinyl-methyloxy)phenyl)-1,3-dithiane (0.01 mol) under N₂ isadded a 5% excess of N-butyl lithium in N -hexane (2.5M) at a rate if3-5 ml/min at -78° C. After 3 hours, 4-cyanobenzylchloride (0.01 mol in20 ml of THF) is added dropwise over a period of 10 minutes. Let stir 3hours at -78° C. and then allow the reaction mixture to come to 0° C.slowly. The mixture is poured into 3 volumes of water, extracted withchloroform furnishing an organic solution which is washed twice withwater, 7% aqueous KOH and again with water. The organic layer is driedover K₂ CO₃ and is concentrated. The crude product is purified by columnchromatography to give the desired product which is used directly in thenext step.

C. 4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile. To a solutionof 2-(3-(2-quinolinylmethyloxy-1,3-dithiane (1.0 mmol) in 80% aqueousacetonitrile (10 ml) is added mercuric chloride (2.2 mmol) as a solutionin the same solvent mixture. Mercuric oxide (1.1 mmol) is then added tobuffer the reaction mixture near pH=7. The dithianemercuric chloridecomplex separates as a white precipitate. The reaction mixture isrefluxed under nitrogen for 5 hours, then cooled and filtered throughSuper Gel. The filter cake is washed thoroughly with 1:1hexane-dichloromethane. The organic phase is washed with 5M aqueousammonium acetate. water and brine. The organic phase is then dried withMgSO₄, and is concentrated to give the crude product which is purifiedby column chromatography to give4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile.

D. 5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole. Aheterogenous mixture of4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile (1.35 mmol). NaN₃(6.77 mmol), pyridinium hydrochloride (6.77 mmol) in DMF (3 ml) isheated at 100° C. for 3 hours under nitrogen. The reaction mixture ispoured into water and the product is collected on a filter.Recrystallization from EtOAc - DMF gives5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole.

EXAMPLE 63

When 3-(2-quinolinylmethyloxy)benzaldehyde in Example 62, Step A isreplaced by the aldehydes of Example 61, and 4-cyanobenzyl chloride ofExample 62, Step B is replaced by the compounds of Table X, Example 29or Table VII, Example 23, then the corresponding products are obtained.Representative compounds prepared by this invention are shown in TableXXI.

TABLE XXI

5-(4-(4-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzyl)tetrazole

5-(3-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)propyl)tetrazole

5-(3-(3-(2-quinolinylmethylthio)benzoylmethyl)phenyl)tetrazole

5-(4-(3-(2-quinolinylmethyloxy)benzoylethyl)benzyl)tetrazole

EXAMPLE 64 5-(3-(3-(2-Quinolinylmethyloxy)Benzoylamino)Phenyl)Tetrazole

A. 3-(2-quinolinylmethyloxy)benzoic acid. A mixture of 28.16 g (0.132mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMFis heated at 70° C. overnight. The reaction mixture is poured intowater, and the precipitated product is collected, filtered and dried togive 3-(2-quinolinylmethyloxy)benzoic acid.

B. 3-(2-quinolinylmethyloxy)benzoic acid chloride. A mixture of 15.6 g(0.1 mol) of 3-(2-quinolinylmethyloxy)benzoic acid and 11.9 g (0.1 mol)of thionyl chloride is refluxed for 4 hours. The reaction mixture isthen evaporated to dryness at room temperature and used directly in thenext step.

C. 3-(3-(2-quinolinylmethyloxy)benzoylamino)benzonitrile. A solution of3-aminobenzonitrile (10 mmol) in 50 ml of chloroform and triethylamine(11 mmol) is added to a solution of 10 mmol of3-(2-quinolinylmethyloxy)benzoic acid chloride in 20 ml of chloroformover a period of 10 minutes. The reaction is stirred at room temperaturefor 2 hours and is poured into water and then extracted into chloroform.The organic solution is dried and evaporated to give3-(3-(2-quinolinylmethyloxy)benzoylamino)-benzonitrile.

D. 5-3-(3-(2-quinolinylmethyloxy)benzoylamino)phenyl)tetrazole. Amixture of 10 mmol of3-(3-(2-quinolinylmethyloxy)benzoylamino)benzonitrile, 50 mmol of sodiumazide, and 50 mmol of pyridine HCl in 30 ml of DMF is heated at 100° C.for 2 days. The reaction mixture is poured into water, and the productis collected on a filter. Recrystallization from ethyl acetate and DMFgives 5-3-(3-(2-quinolinylmethyloxy)benzoylamino)phenyl)tetrazole.

In a similar manner, the compounds of this invention where B is##STR19## may be made.

EXAMPLE 655-3-(3-(2-Quinolinylmethyloxy)Anilinocarbonyl)Phenyl)Tetrazole

When the procedure of Example 64 is followed and3-(2-quinolinylmethyloxy)aniline is used in place of 3-aminobenzonitrileand 3-cyanobenzoic acid is used in place of 3-(2-quinolinylmethyloxy)benzoic acid, then the product prepared is5-3-(3-(2-quinolinylmethyloxy)anilinocarbonyl)phenyl)tetrazole.

In a similar manner, the compounds of this invention where B is##STR20## may be made.

The methods described above are used to prepare the following compoundsof this invention.

5-[2-(4-(2-Quinolinylmethyloxy)phenoxymethyl)benzyl]tetrazole (M.P.)108°-111° C.) CALC: C, 59.87; H, 5.96; N, 13.96; FOUND: C, 59.67, 60.01;H, 5.62, 5.63; N, 13,73, 13.77.

5-[4-Methoxy-3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl]tetrazole(M.P. 184°-87° C.)

CALC: C, 67.63; H, 4.88; N, 15.78; FOUND: C, 67.18; H, 5.13; N, 15.40.

5-[3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenyl]tetrazole (M.P.176°-177° C.)

CALC: C, 69.63; H, 4.75; N, 16.92; FOUND: C, 69.58, 60,64; H, 5.00,4.98; N, 16.66, 16.63

5-[3-Methoxy-4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole(M.P. 195°-97° C.)

CALC: C, 67.63; H, 4.88; N, 15.77; FOUND: C, 67.27; H, 4.89; N, 15.41.

5-[4-(3-(2-quinolinylmethyloxy)phenoxymethyl)-3-methoxyphenyl]-tetrazole(M.P. 189°-91° C.)

CALC: C, 66.95; H, 4.95; N, 15.61; FOUND: C, 66.48; H, 5.14; N, 14.93.

5-[3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)benzyl]tetrazole(M.P. 139°-44° C.)

CALC: C, 70.53; H, 5.03; N, 16.45; FOUND: C, 70.33, 70.54; H, 5.25,5.36; N, 16.38, 16.41.

5-[4-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzyl]tetrazole (M.P.167°-71° C.)

CALC: C, 67.33; H, 5.31; N, 15.70; FOUND: C, 67.54, 67.67; H, 5.33,5.33; N, 15.48, 15.52.

5-[4-Methoxy-3-(4-(2-quinolinylmethyloxy)phenylmethyloxy)phenyl]tetrazole(M.P. 210°-13° C.)

CALC: C, 68.33; H, 4.82; N, 4.90; FOUND: C, 68.32; H, 4.90; N, 14.79.

4-[3-(2-Quinolinylmethyloxy)phenoxymethyl]phenoxyacetic acid (M.P. 164(dec))

CALC: C, 69.27; H, 5,35; N, 3.23; FOUND: C, 69.53, 69.65; H, 5.11, 5.05;N, 3.21, 3.12.

5-[2-(4-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxymethyl]tetrazole(M.P. 183°-85° C.)

CALC: C, 65.63; H, 5.08; N, 15.31; FOUND C. 65.77, 65.52; H, 4.99, 5.03;N, 14.92, 15.03.

4-[4-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxyacetic acid (176° C.(dec))

CALC: C, 71.50; H, 5.16; N, 3.34; FOUND: C, 71.10, 71.17; H, 5.27, 5.33;N, 3.37, 3.34.

4-[3-(2-Quinolinylmethyloxy)phenoxymethyl]phenylacetic acid (M.P.158°-60° C.)

CALC: C, 75.17; H, 5.30; N, 3.51; FOUND: C, 74.89; H, 5.36; N, 3.37.

2-[3-(3-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxy]pentanoic acid(M.P. 133°-35° C.)

CALC: C, 73.51; H, 5.95; N, 3.06; FOUND: C, 73.35, 73.60; H, 5.95, 5.98;N, 3.08, 3.05.

2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]phenoxyacetic acid (M.P.169°-172° C.)

CALC: C, 72.28; H, 5.10; N, 3.37; FOUND: C, 69.34, 69.69; H, 5.10, 5.13;N, 3.00, 3.08; CALC: C, 69.27; H, 5.35; N, 3.23 (as Hydrate).

2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]cinnamic acid (M.P. 175°-178°C.)

CALC: C, 75.90; H, 5.14; N, 3.40; FOUND: C, 73.92; H, 5.20; N, 3.01;CALC: C, 74.27; H, 5.27; N, 3.33 (as Hydrate).

6-Acetyl-2-propyl-3-[3-(2-quinolinylmethyloxy)benzyloxy]phenoxyaceticacid (M.P. 153°-58° C.)

CALC: C, 72.13; H, 5.85; N, 2.90; FOUND: C, 71.68, 72.08; H, 5.88, 5.83;N, 2.65, 2.70.

2-[2-(4-(7-Chloroquinolin-2-ylmethyloxy)phenoxymethyl)phenoxy]propionicacid (M.P. 169°-173° C.)

CALC: C, 67.32; H, 4.78; N, 3.02; CI, 7.64; FOUND: C, 65.18; H, 4.90; N,2.84; CI, 8.33; CALC: C, 65.41; H, 4.96; N, 2.93; CI, 7.42 (as HYDRATE).

2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]phenylacetic acid (M.P.181°-83° C.)

CALC: C, 75.17; H, 5.30; N, 3.51; FOUND: C, 75.12, 74.96; H, 5.50, 5.49;N, 3.16, 3.16.

3-[3-(2-Quinolinylmethyloxy)phenoxymethyl]phenoxyacetic acid (M.P.146°-51° C.)

CALC: C, 72.28; H, 5.10; N, 3.37; FOUND: C, 71.82, 71.80; H, 5.24, 5.23;N, 2.98, 3.00; CALC: C, 71.50; H, 5.16; N, 3.34 (as HYDRATE).

2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]phenoxyacetic acid (M.P.153°-57° C.)

CALC: C, 72.28; H, 5.10; N, 3.37; FOUND: C, 72.30, 71.72; H, 5.39, 5.30;N, 2.94, 2.89.

5-[2-(4-(7-Chloroquinolin-2-ylmethyloxy)phenoxymethyl)benzyl]tetrazole(M.P. 159°-63° C.)

CALC: C, 65.57; H, 4.40; N, 15.29; FOUND: C, 64.16; H, 4.72; N, 14.98;CALC: C, 64.30; H, 4.53; N, 14.99 (as HYDRATE)

2-Carbomethoxy-5-[3-(2-quinolinylmethyloxy)phenoxymethyl]phenoxyaceticacid (M.P. 187°-89° C.)

CALC: C, 68.49; H, 4.90; N, 2.95; FOUND: C, 66.71; H, 4.96; N, 2.70;CALC: C, 66.59; H, 5.07; N, 2.87(as HYDRATE).

2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]-6-methylphenoxyacetic acid(M.P. 149°-53° C.)

CALC: C, 72.71; H, 5.40; N, 3.26; FOUND: C, 71.23; H, 5.46; N, 3.08;CALC: C, 71.22; H, 5.51; N, 3.19 (as HYDRATE).

2-[3-(3-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxy]glutaric acid (M.P.129°-30° C.)

CALC: C, 69.00; H, 5.17; N, 2.87; FOUND: C, 58.19; H, 4.93; N, 2.23;CALC: C, 58.23; H, 5.17; N, 2.43 (as HYDRATE).

2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]benzylmalonic acid (M.P.164°-65° C.)

CALC: C, 70.89; H, 4.08; N, 3.06; FOUND: C, 70.51, 70.61; H, 5.03, 5.24;N, 3.03, 2.90.

2-[2-(3-Quinolinylmethyloxy)phenoxymethyl)phenoxy]pentanoic acid (M.P.118°-20° C.)

CALC: C, 73.51; H, 5.95; N, 3.06; FOUND: C, 73.26; H, 6.07; N, 2.79.

2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]-6-methylphenoxy acetic acid(M.P. 151°-53° C.)

CALC: C, 72.71; H, 5.40; N, 3.26; FOUND: C, 71.41; H, 5.58; N, 3.03;CALC: C, 71.22; H, 5.51; N, 3.19 (as HYDRATE).

2-[2-(4-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxy]pentanoic acid(M.P. 85°-92° C.)

CALC: C, 73.51; H, 5.95; N, 3.06; FOUND: C, 71.73, 71.79; H, 5.96, 5.91;N, 3.06, 2.83; CALC: C, 72.09; H, 6.05; N, 3.00 (as HYDRATE).

2-Carbomethoxy -5-[4-(2-quinolinylmethyloxy)phenoxymethyl]phenoxyaceticacid (M.P. 149°-51° C.)

CALC: C, 68.49; H, 4.90; N, 2.95; FOUND: C, 68.00, 68.08; H, 4.98, 5.04;N, 2.90, 2.90.

2-[2-(4-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxy]propionic acid(M.P. 161°-64° C.)

CALC: C, 72.71; H, 5.40; N, 3.26; FOUND: C, 70.96, 71.10 ; H, 5.51,5.58; N, 3.08, 3.10; CALC: C, 71.22; H, 5.52; N, 3.19 (as HYDRATE).

2-[2-(3-(2-Quinolinylmethyloxy)phenoxymethyl)phenoxy]glutaric acid (M.P.83° C.)

CALC: C, 68.98; H, 5.17; N, 2.87; FOUND: C, 64.10, 63.75; H, 4.89, 4.92;N, 2.64, 2.69; CALC: C, 63.74; H, 5.63; N, 2.65(as HYDRATE).

2-(3-[2-Quinolinylmethyloxy]benzyloxy)phenoxyacetic acid (M.P. 153°-55°C.)

CALC: C, 72.28; H, 5.10; N, 3.37; FOUND: C, 71.75; H, 5.14; N, 3.38;CALC: C, 71.50; H, 5.16; N, 3.34 (as HYDRATE).

2-[2-(4-(2-Quinolinylmethyloxy)phenoxymethyl]-4-chlorophenoxy)propionicacid (M.P. 196°-99° C.)

CALC: C, 67.32; H, 4.78; N, 3.02; FOUND: C, 67.40, 67.43; H, 4.89, 4.94;N, 3.01, 3.13.

2-[2-(3-(2-Quinolinylmethyloxy)phenoxymethyl]-4-chlorophenoxy)propionicacid (M.P. 169°-71° C.)

CALC: C, 67.32; H, 4,78; N, 3.02; FOUND: C, 65.47; H, 5.31; N, 2.78;CALC: C, 65.41; H, 4.96; N, 2.93(as HYDRATE).

2-(2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]-4-chlorophenoxy)pentanoicacid (M.P. 144°-4520 C.)

CALC: C, 68.36; H, 5,33; N, 2.85; FOUND: C, 67.74, 67.86; H, 5.39, 5.47;N, 2.91, 2.84; CALC: C, 67.74; H, 5.38; N, 2.82(as HYDRATE).

2-(2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]-4-chlorophenoxy)pentanoicacid (M.P. 155°-56° C.)

CALC: C, 68.36; H, 5.33; N, 2.85; FOUND: C, 65.96; H, 5.59; N, 2.66;CALC: C, 65.95; H, 5.53; N, 2.75(as HYDRATE).

2-(2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]-4-chlorophenoxy)pentanoicacid (M.P. 155°-56° C.)

CALC: C, 68.36; H, 5.33; N, 2.85; FOUND: C, 66.15; H, 5.58; N, 2.68;CALC: C, 65.95; H, 5.53; N, 2.75(as HYDRATE).

2-(2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]-6-chlorophenoxy)pentanoicacid (M.P. 161°-62° C.)

CALC: C, 68.36; H, 5.33; N, 2.85; FOUND: C, 68.15; H, 5.36; N, 2.72.

2-(2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]-6-chlorophenoxy)pentanoicacid (M.P. 169°-70° C.)

CALC: C, 68.36; H, 5.33; N, 2.85; FOUND: C, 68.10; H, 5.39; N, 2.72.

2-(2-[3-(2-Quinolinylmethyloxy)phenoxymethyl]-6-chlorophenoxy)-4-methylpentanoicacid (M.P. 164°-66° C.)

CALC: C, 68.84; H, 5.58; N, 2.77; FOUND: C, 68.84; H, 5.70; N, 2.69.

2-(2-[4-(2-Quinolinylmethyloxy)phenoxymethyl]-6-chlorophenoxy)-4-methylpentanoicacid (M.P. 167°-69° C.)

CALC: C, 68.84; H, 5.58; N, 2.77; FOUND: C, 68.78; H, 5.67; N, 2.68.

5-[3-(3-(2-Quinolinylmethyloxy)benzyloxy)-4-methoxyphenyl]tetrazole(M.P. 204°-07° C.)

CALC: C, 67.63; H, 4.88; N, 15.78; FOUND: C, 67.11; H, 5.15; N, 15.86

N-[3-Methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoyl benzenesulphonamide hydrochloride (M.P. dec.88)

CALC: C, 62.99; H, 4.60; N, 4,74; FOUND: C, 63,88; H, 5.13; N, 4.80;

5-Carboxy-2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy acetic acid(M.P. 226°-28° C.)

CALC: C, 61.90; H, 5.18; N, 2.77; FOUND: C, 61.62; H, 5.11; N, 2.67.

5-[3-Methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole(M.P. 204°-05° C.)

CALC: C, 67.67; H, 5.14; N, 15.87; FOUND: C, 67.63; H, 4.88; N, 15.78.

5-4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)tetrazole (M.P. 233°-36°C.)

CALC: C, 69.58; H, 4.73; N, 16.91; FOUND: C, 69.59; H, 4.89; N, 16.91.

Using a combination of the above Examples, various compounds may be madewithin the scope of this invention.

We claim:
 1. A compound of the formula ##STR21## where: A is O or S;B isO, S, SO, SO2NR₁, ##STR22## D is O, S, NR, ##STR23## or a chemical bond;E is a chemical bond or ##STR24## a is 0-2; b is 0-1; c is 0-4; d is0-5; e is 0-4; f is 0-5; n is 0-2; R is independently hydrogen, alkyl,hydroxy, alkoxy, carboxy, carbalkoxy, halo, nitro, haloalkyl, cyano oracyl; R' is independently hydrogen, alkyl, hydroxy, alkoxy, halo orhaloalkyl; R₁ is independently hydrogen, alkyl or aralkyl; R₂ is--(CH2)_(x) --X, where x is 0-3; X is hydrogen, alkyl, alkenyl,cycloalkyl, aryl aralkyl, hydroxy, alkoxy, aralkoxy, amino, mono-anddi-alkylamino, aralkylamino, acylamino, carbamyl, carboxy, carbalkoxy,tetrazolyl, or acylsulfonamido; vicinal R₂ groups together may be(CH₂)_(y) -- where y is 1-4, thus forming a 3-6 membered ring; geminalR₁ and R₂ groups may together form a spiro substituent, --(CH₂)_(z) --,were z is 2 to 5; geminal R₁ or R₁ and R₂ groups may together form analkylidenyl substituent, ═CHR₁ ; Z is --COOR₁, CN, ##STR25## --OR₁,tetrazolyl or substituted tetrazolyl where the substituent may be alkyl,carboxyalkyl or carbalkoxyalkyl; and R₃ is hydrogen, alkyl, haloalkyl,phenyl or benzyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 where:A is O or S; B is O or S; n is 0-1;a+b is 1; c+d is 1-2; e+f is 0-5; R and R' are hydrogen, alkyl oralkoxy; R₁ is hydrogen or alkyl; R₂ is --(CH₂)_(x) --X where x is 0-3and X is hydrogen or alkyl; and Z is --COOR₁, --CN, ##STR26## ortetrazolyl.
 3. A compound according to claim 2 where:A and B are O; n is0; c+d is 1; and Z is --COOR₁, --CN or tetrazolyl.
 4. A compoundaccording to claim 3 where:a is 1; b is 0; c is 1; and d is
 0. 5. Acompound according to claim 4 where: D is O; and E is a chemical bond.6. A compound according to claim 4 where:D is S; and E is a chemicalbond.
 7. A compound according to claim 4 where:e+f is 0; D is a chemicalbond; and E is a chemical bond.
 8. A compound according to claim 4where:e+f is 1-5; D is a chemical bond; and E is a chemical bond.
 9. Acompound according to claim 4 where:D is O; and E is ##STR27##
 10. Acompound according to claim 4 where:D is a chemical bond or ##STR28##and E is ##STR29##
 11. A compound according to claim 3 where:a is 1; bis 0; c is 0; and d is
 1. 12. A compound according to claim 2 where:is1; b is 0; c is 0; and d is
 2. 13. A compound according to claim 11where:D is O; and E is a chemical bond.
 14. A compound according toclaim 11 where:c+f is 0; D is a chemical bond; and E is a chemical bond.15. A compound according to claim 13 where e+f is 1-5.
 16. A compoundaccording to claim 7 which is5-(3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl)tetrazole or apharmaceutically acceptable salt thereof.
 17. A compound according toclaim 7 which is5-[4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)phenyl]tetrazoleor a pharmaceutically acceptable salt thereof.
 18. A compound accordingto claim 7 which is5-[3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 19. A compound according toclaim 7 which is5-[4-methoxy-3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 20. A compound according toclaim 7 which is5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 21. A compound according toclaim 8 which is5-[4-(4-(2-quinolinylmethyloxy)benzyloxy)benzyl]tetrazole or apharmaceutically acceptable salt thereof.
 22. A compound according toclaim 8 which is5-[4-(3-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl)-3-methylbutyl]tetrazoleor a pharmaceutically acceptable salt thereof.
 23. A compound accordingto claim 14 which is5-[3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 24. A compound according toclaim 14 which is5-[2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 25. A compound according toclaim 14 which is5-[4-(3-(2-quinolinylmethyloxy)phenoxymethyl))phenyl]tetrazole or apharmaceutically acceptable salt thereof.
 26. A compound according toclaim 14 which is 4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzonitrileor a pharmaceutically acceptable salt thereof.
 27. A compound accordingto claim 14 which is 4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoicacid or a pharmaceutically acceptable salt thereof.
 28. A compoundaccording to claim 14 which is3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid or apharmaceutically acceptable salt thereof.
 29. A compound according toclaim 15 which isα-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile or apharmaceutically acceptable salt thereof.
 30. A compound according toclaim 15 which is5-[4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl]tetrazole ora pharmaceutically acceptable salt thereof.
 31. A compound according toclaim 15 which is5-[4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl]tetrazole ora pharmaceutically acceptable salt thereof.
 32. A compound according toclaim 15 which is5-[3-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl]tetrazole ora pharmaceutically acceptable salt thereof.
 33. A compound according toclaim 15 which is5-carboxy-2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxyacetic acidor a pharmaceutically acceptable salt thereof.
 34. A compound accordingto claim 15 which is5-[2-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl]tetrazole ora pharmaceutically acceptable salt thereof.
 35. A compound according toclaim 15 which is5-[2-(3-(2-quinolinylmethyloxy)phenoxymethyl)5-carbomethoxyphenoxymethyl]tetrazoleor a pharmaceutically acceptable salt thereof.
 36. A compound accordingto claim 7 which is3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid or apharmaceutically acceptable salt thereof.
 37. A compound according toclaim 7 which is methyl3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoate or apharmaceutically acceptable salt thereof.
 38. A compound according toclaim 2 which is5-[3-methoxy-4-(3-(2-quinolinylmethyloxy)phenyoxymethyl)phenyl]tetrazoleor a pharmaceutically acceptable salt thereof.
 39. A compound accordingto claim 2 which isN-[3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoyl]benzenesulfonamide or a pharmaceutically acceptable salt thereof.
 40. Acompound according to claim 14 which is3-methoxy-4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid or apharmaceutically acceptable salt thereof.
 41. A compound according toclaim 1 which is5-[2-(4-(2-quinolinylmethyloxy)phenoxymethyl)benzyl]tetrazole or apharmaceutically acceptable salt thereof.
 42. A method for the treatmentof hypersensitive ailments in humans and mammals comprisingadministering thereto an effective amount of a compound of the formulaaccording to claim
 1. 43. A pharmaceutical composition wherein theactive ingredient is a compound according to claim 1 in admixture with apharmaceutical carrier.